1-amino-3(or4)-phenyl-3,4-dehydroisoquinolines

ABSTRACT

3,4-Dihydroisoquinoline derivatives of the formula:-   WHEREIN THE SYMBOLS R represent hydrogen, halogen or methoxy, or together form the methylenedioxy radical, the symbols R1 and R2 represent hydrogen or phenyl, at least one of the symbols R1 and R2 representing phenyl, the symbol A represents an alkylene radical, and (a) the symbols R3 and R4 represent alkyl, or (b) R3 represents alkylene forming a nitrogen-containing heterocyclic ring by attachment to a carbon atom of the alkylene radical A, and R4 represents alkyl, or (c) the symbols R3 and R4 together with the nitrogen atom form a mononuclear heterocyclic group optionally substituted by alkyl, are useful as anti-arhythmic agents.

United States Patent 1 1 Jeanmart et al.

[ 1 Sept. 18, 1973 1-AM 1N0-3(0R4)-PHENYL-3,4-

DEHYDROISOQUINOLINES [75] Inventors: Claude Jeanmart, Brunoy; MayerNaoum Messer, Dievres; Pierre Simon, Hauts-de-Seine, all of France [30]Foreign Application Priority Data Mar. 12, 1970 France 7008932 [56]References Cited UNITED STATES PATENTS 10/1966 Aebi 260/288 R 5/1971Ehrhart 2/1972 Jeanmart et al. 3/1972 Gittos et a1. 260/288 R PrimaryExaminer-Donald G. Daus AttorneyStevens, Davis Miller & Mosher [57]ABSTRACT 3,4-Dihydroisoquinoline derivatives of the formula:-

wherein the symbols R represent hydrogen, halogen or methoxy, ortogether form the methylenedioxy radical, the symbols R and R representhydrogen or phenyl, at least one of the symbols R, and R, representingphenyl, the symbol A represents an alkylene radical, and (a) the symbolsR and R represent alkyl, or (b) R, represents alkylene forming anitrogen-containing heterocyclic ring by attachment to a carbon atom ofthe alkylene radical A, and R represents alkyl, or (c) the symbols R andR together with the nitrogen atom form a mononuclear heterocyclic groupoptionally sub stituted by alkyl, are useful as anti-arhythmic agents.

9 Claims, No Drawings 1 l-AMlNO-3(OR4 )-PHENYL-3,4-

DEHYDROISOQUINOLINES THIS INVENTION relates to new therapeuticallyuseful derivatives of 3,4-dihydroisoquinoline, to a process for theirpreparation and pharmaceutical compositions containing them.

The new 3,4-dihydroisoquinoline derivatives of the present invention arethose of the general formula:

(wherein the symbols R are the same or different and each represents ahydrogen or halogen atom or a methoxy radical or together form amethylenedioxy radical, preferably both symbols represent hydrogenatoms, the symbols R, and R are the same or different and eachrepresents a hydrogen atom or a phenyl radical, at least one of thesymbols R, and R representing a phenyl radical, the symbol A representsa straightor branched-chain alkylene radical containing 1 to 5 carbonatoms, eg an ethylene or 2-methylethylene group, and (a) the symbols Rand R are the same or different and each represents an alkyl radicalcontaining I to 5 carbon atoms (preferably methyl or ethyl), or (b) Rrepresents an alkylene radical containing at most 5 carbon atoms forminga ring with at most 7 atoms in it by attachment to a carbon atom of thealkylene radical A, the ring being thus a nitrogen-containingheterocyclic ring, such as Z-piperidyl, 3-piperidyl or 4-piperidyl, andR represents an alkyl radical containing I to 5 carbon atoms, an exampleof such a combination being 1- ethyl-3 -piperidyl, or (c) the symbols R,and R together with the nitrogen atom to which they are attached form a5' or 6-membered mono-nuclear heterocyclic group, optionally containinga second hetero atom selected from nitrogen, oxygen and sulphur atoms,and optionally substituted by an alkyl radical containing l to 5 carbonatoms, such as l-pyrrolidinyl, piperidino, morpholino or4-methyl-l-piperazinyl) and acid addition and quaternary ammonium saltsthereof. Preferred compounds of the invention are those in which one ofR, and R represents a hydrogen atom and the other represents a phenylgroup, and especially 3- phenyl- 1 -[2-( l-pyrrolidinyl)-ethylamin]-3,4-dihydroisoquinoline and acid addition and quaternary ammonium saltsthereof.

According to a feature of the invention, the 3,4- dihydroisoquinolinederivatives of general formula I are obtained by the process whichcomprises reaction of an amine of the general formula:

B4 II (wherein A, R, and R are as hereinbefore defined) with a 3,4-dihydroisoquinoline derivative of the general formula:

(wherein R, R, and R, are ashereiinbefore defined, and R represents analkyl radical containing 1 to 3 carbon atoms, preferably the methylradical) or an acid addition salt thereof, preferably the hydriodide.

When the 3,4-dihydroisoquinoline starting material of general formulaIII is used in the form of the free base, the reaction is preferablyeffected by heating the reactants in an inert organic solvent, such asethanol, toluene or dimethylformamide, at a temperature be tween 50 C.and the boiling point of the reaction mixture. It is particularlyadvantageous to carry out the reaction under an inert atmosphere such asa nitrogen atmosphere. The reaction is generally complete after a periodof heating of between 10 and 30 When the starting material of generalformula III is used in the form of an acid addition salt, it ispreferable to carry out the reaction in an alcohol, for example ethanol,and at a temperature between 50 and C. for 30 minutes to 10 hours.

The 3,4-dihydroisoquinoline derivatives of general formula III can beprepared by cyclisation of an isothiocyanate of the general formula:

III

(wherein R, R, and R are as hereinbefore defined), I

followed by S-alkylation by methods known per se of the resulting l,2,3,4-tetrahydroisoquinoline- 1 -thione. By the term methods known perse" as used in this specification is meant methods heretofore used ordescribed in the chemical literature. The cyclisationof theisothiocyanate is generally carried out by heating in sulphuric acid orpolyphosphoric acid, or by the action of aluminium chloride inn-heptane.

The 3,4-dihydroisoquinoline derivatives of general formula I obtained bythe aforementioned process can be purified by physical methods such asdistillation, crystallisation or chromatography, or by chemical methodssuch as the formation of salts, crystallisation of the salts anddecomposition of them in an alkaline medium. In carrying out the saidchemical methods the nature of the anion of the salt is immaterial, theonly requirement being that the salt must. be well-defined and readilycrystallisable.

The 3,4-dihydroisoquinoline derivatives of general formula I may beconverted by methods known per se into acid addition and quaternaryammonium salts. The acid addition salts may be obtained by the action ofacids on the dihydroisoquinoline derivatives in appropriate solvents. Asorganic solvents there may be used alcohols, ketones, ethers orchlorinated hydrocarbons. The salt which is formed is precipitated, ifnecessary after concentration of the solution, and is isolated byfiltration or decantation. The quaternary ammonium salts may be obtainedby the action of esters on the dihydroisoquinoline bases, optionally inan organic solvent, at room temperature or, more rapidly, with gentleheating.

The 3,4-dihydroisoquinoline derivatives of the present invention, andtheir acid addition and quaternary ammonium salts, possess interestingpharmacodynamic properties; they are very active as anti-arythmicagents. In vitro, at concentrations of between 1 and mg./litre, theyhave proved active in a study of the prolongation of the refractoryperiod of the isolated auricles of the rabbit [G.S. Dawes, Brit. J.PharmacoL, 1, 90 (1946)]. In vivo, the products have proved active inrabbits against electrocardiographic abnormalities caused by aconitine,and in guinea pigs against the cardiac toxicity of ouabain [A. Seyikaand EM. Vaughan Williams, Brit. J. Pharmacol., 21, 462 (1963)] at dosesof between 0.5 and 10 mg./kg. animal body weight administeredintravenously.

For therapeutic purposes, the 3,4- dihydroisoquinoline derivatives ofgeneral formula 1 may be employed as such or in the form of non-toxicacid addition salts, i.e., salts containing anions which are relativelyinnocuous to the animal organism in therapeutic doses of the salts (suchas hydrochlorides, sulphates, nitrates, phosphates, acetates,propionates, succinates, benzoates, fumarates, maleates, tartrates,theophyllineacetates, salicylates, phenolphthalinates andmethylene-bis-B-hydroxynaphthoates) so that the beneficial physiologicalproperties inherent in the bases are not vitiated by side-effectsascribable to the anions. However, they may also be employed in the formof non-toxic quaternary ammonium salts obtained by reaction with organichalides e.g. methyl, ethyl, ally] or benzyl chloride, bromide or iodide,or other reactive esters, e.g. methylor ethyl-sulphates, benzenesulphonates or toluene-p-sulphonates.

The following Examples illustrate the invention.

EXAMPLE 1 A solution of 1-methylthio-3-phenyl-3,4- dihydroisoquinolinehydriodide (14.8 g.), 96 percent 2-diethylamino-propylamine (5.6 g.) and7.8N hydriodic acid (5.5 cc.) in ethanol (85 cc.) is heated under refluxfor 2 hours. A product crystallises, and is filtered off and washed withethanol (10 cc.) and then with diethyl ether (3 X 10 cc.). l-(2-Diethylaminopropylamino)-3-phenyl-3,4- dihydroisoquinoline dihydriodide(17.1 g.), melting at about 140 C. with decomposition, is thus obtained.

2-Diethylaminopropylamine can be prepared according to V. Prelog, Helv.Chim. Acta, 26, 1172 (1943).

l-Methylthio-3-phenyl-3 ,4-dihydroisoquinoline hydriodide can beprepared as follows:

A solution of 3-phenyl-l,2,3,4-tetrahydroisoquinoline-l-thione (74.4 g.)and methyl iodide (66.2 g.) in acetone (600 cc.) is heated under refluxfor 2 hours. A product crystallises, and is filtered off and washed withacetone (100 cc.) and then with diethyl ether (100 cc.l-Methylthio-3-phenyl-3 ,4-dihydroisoquinoline hydriodide (109.2 g.),melting at l90200 C. with decomposition, is thus obtained.

The 3-phenyll ,2,3 ,4-tetrahydroisoquinolinel thione can be obtained bycyclisation of 1- isothiocyanato-1,2-diphenylethane (438 g.) inconcentrated sulphuric acid (d 1.83; 2200 g.) for 1 hour at 55 C. Themixture is poured into water (2000 cc.), ground ice (400 g.) andmethylene chloride (2000 cc.). The organic phase is separated and theaqueous phase is extracted with methylene chloride (2 X 2000 cc.).

The combined organic phases are washed successively with water (2000cc.), a 4 percent (w/v) aqueous sodium bicarbonate solution (2000 cc.),and water (2000 cc.), and then dried over sodium sulphate. Afterfiltration, the solvent is evaporated under reduced pressure (30 mm.Hg).The residue 187 g.) is dissolved in benzene (1800 cc.), and the solutionis poured into a column, 7.5 cm. in diameter, containing silica (1800g.). Elution with benzene containing 10 percent (v/v) of ethyl acetate(5400 cc.) yields 3-phenyl-1,2,3,4- tetrahydroisoquinoline-l-thione g.)melting at l35-138 C.

l-Isothiocyanato-l,2-diphenylethane can be prepared according to 1.A.Kaye and CL. Parris, J. Amer. Chem. Soc., 74, 1566 (1952).

EXAMPLE 2 A solution of l-methylthio-3-phenyl-3 ,4- dihydroisoquinolinehydriodide (7.6 g.), 92 percent l-(2-aminoethyl)-pyrrolidine (2.7 g.)and 7.8N hydriodic acid (2.9 cc.) in ethanol (45 cc.) is heated underreflux for 2 hours. The product which crystallises is filtered off andwashed with diethyl ether (2 X 10 cc.). 3-Phenyl-1-[2-(1-pyrrolidinyl)-ethylamino]-3,4- dihydroisoquinoline dihydriodide (9.6g.), melting at 196 C., is thus obtained.

1-(2 aminoethyl)-pyrrolidine can be prepared according to J. Van Alphen,Rec. Trav. Chim., 58, 1105 (1939).

EXAMPLE 3 A solution of 1 -methylthio-3-phenyl-3 ,4- dihydroisoquinolinehydriodide (14.8 g.), 2-diethylaminoethylamine (5 g.) and 7.8N hydriodicacid (5.5 cc.) in ethanol (85 cc.) is heated under reflux for 2 hours.The product which crystallises is filtered off and washed with ethanol(10 cc.) and then with acetone (2 X 20 cc.).1-(2-Diethylamino-ethylamino)-3- phenyl-3,4-dihydroisoquinolinedihydriodide (17.2 g.), melting at 212 C., is thus obtained.

EXAMPLE 4 A solution of l-methylthio-4-phenyl-3,4-dihydroisoquinolinehydriodide (38.1 g.), l-ethyl-3-aminopiperidine 14.1 g.) and 7.8Nhydriodic acid (14.1 cc.) in ethanol (500 cc.) is heated under refluxfor 9 hours. The solvent is evaporated under reduced pressure (30 mm.Hg)and the residue obtained is treated with water (250 cc.), 10N sodiumhydroxide solution cc.) and methylene chloride (250 cc.). The aqueousphase is decanted and then extracted with methylene chloride (300 cc.).The combined organic phases are extracted with N methanesulphonic acid(450 cc.). The acid extracts are made alkaline by addition of ION sodiumhydroxide solution (100 cc.), and the oil which separates is extractedwith methylene chloride (450 cc.). The organic phase is separated,washed with distilled water 100 cc.) and dried over sodium sulphate.Evaporation of the solvent under reduced pressure (30 mm.1-lg) yields ayellow oil (14 g.). This oil is dissolved in ethyl acetate cc.) and thesolution obtained is treated with decolourising charcoal (0.2 g.) andthen filtered. Maleic acid (4.1 g.) dissolved in ethyl acetate (120 cc.)

is added to this solution. The product which crystallises is filteredoff and washed with diethyl ether (50 cc. A product (15.5 g.) is thusobtained, which after two recrystallisations from methyl ethyl ketone(250 cc. followed by 150 cc.) yields l-( l-ethyl-3-piperidyl)-amino-4-phenyl-3,4-dihydroisoquinoline maleate l 1.2 g.), melting at 160C.

l-Methylthio-4-phenyl-3,4-dihydroisoquinoline hydriodide can be preparedby heating a solution of 4- phenyll ,2,3,4-tetrahydroisoquinoline- 1-thione 155.6 g.) and methyl iodide (61 cc.) in acetone (1300 cc.) underreflux for one hour. The product which crystallises is filtered off,washed with acetone (100 cc.) and diethyl ether (100 cc.) and dried. l-Methylthio-4- phenyl-3,4-dihydroisoquinoline hydriodide (130.4 g.),melting at 185 C., is thus obtained.

4-Phenyll ,2 ,3 ,4-tetrahydroisoquinolinel -thione can be prepared byadding l,1-dipheny1-2-isothiocyanatoethane (472 g.) to 97 percentsulphuric acid (1400 cc.) maintained at 30 C., and stirring for afurther hour at 40 C. Thereafter, the reaction mixture is poured into amixture of distilled water (3000 cc.) and ice (3.5 kg.). The productwhich precipitates is extracted with methylene chloride (6000 cc.). Theorganic phase is separated, successively washed with distilled water(2000 cc.), N sodium hydroxide solution (2000 cc.) and distilled water(4000 cc.), dried over sodium sulphate, treated with decolourisingcharcoal (20 g.) and then filtered. Thereafter, the solvent isevaporated under reduced pressure (30 mm.Hg). The product obtained istreated with isopropanol (3000 cc.) under reflux. A yellow insolublematerial is separated by filtration, the filtrate is then treated withdecolourising charcoal (20 g.). After filtration and cooling, an orangeproduct crystallises and is filtered off, washed with isopropanol (100cc.) and then with diisopropyl ether (300 cc.), and dried.4-Phenyll,2,3,4-tetrahydroisoquinoline-l-thione (155.6 g.), melting at128 C., is thus obtained.

1,l-Diphenyl-2 isothiocyanatoethane can be prepared by adding lON sodiumhydroxide solution (580 cc.) to a vigorously stirred mixture of 2,2-diphenylethylamine hydrochloride (474 g.) dissolved in distilled water(5000 cc.) and of thiophosgene (164 cc.) dissolved in methylene chloride(2500 cc.). During the addition of the sodium hydroxide solution, thetemperature is kept at about C. and the pH is kept at below 8. Themixture is stirred for a further hour at about 3 C., the organic phaseis then separated, and the aqueous phase is again extracted withmethylene chloride (2 X 750 cc.). The organic phases are successivelywashed with N hydrochloric acid (750 cc.), distilled water (750 cc.),saturated aqueous sodium bicarbonate solution (750 cc.) and distilledwater (2 X 750 cc.). After drying the solution over sodium sulphate andtreatment with decolourising charcoal (30 g.), the solvent is evaporatedunder reduced pressure (30 mm.Hg). l,1-Diphenyl-2-isothiocyanatoethane(477 g.) is thus obtained.

1,1-Diphenylethylamine can be prepared according to the processdescribed by H. Lettre and H. Wick, Ann. 603, 189 (1957).

l-Ethyl-3-aminopiperidine can be prepared according to the processdescribed by M. Asano and K. Tomita, J. Pharrn. Soc. Japan, 68, 224(1948).

EXAMPLE 5 A solution of l-methylthio-4-phenyl-3,4-dihydroisoquinolinehydriodide 20 g. 2-

diethylaminopropylamine (7.6 g.) and 7.8N hydriodic acid (7.5 cc.) inethanol (200 cc.) is heated under reflux for 2 hours. On cooling, awhite product crystallises, and is filtered off and washed with ethanol(10 cc.) and diethyl ether (60 cc.). A product (23.2 g.) melting, withdecomposition, at between 175 and 1 C. is thus obtained. Afterrecrystallisation from ethanol cc.), l-(2-diethylaminopropylamino)-4-phenyl- 3,4-dihydroisoquinolinedihydriodide (12.1 g.), melting at C. with decomposition, is obtained.

2-Diethylaminopropylamine can be prepared according to V. Prelog, Helv.Chim. Acta, 26, 1172 (1943).

The present invention includes within its scope pharmaceuticalcompositions containing, as active ingredient, at least one of the3,4-dihydroisoquinoline derivatives of general formula I, or a non-toxicacid addition or quaternary ammonium salt thereof, in association with apharmaceutical carrier or coating. The invention includes especiallysuch preparations made up for oral, parenteral or rectal administrationor local application, e.g. as ointments. 1

Solid compositions for oral administration include tablets, pills,powders, and granules. ln such solid compositions the active compound isadmixed with at least one inert diluent such as sucrose, lactose orstarch. The compositions may also comprise, as is normal practice,additional substances other than inert diluents, e.g. lubricatingagents, such as magnesium stearate. Liquid compositions for oraladministration include pharmaceutically-acceptable emulsions, solutions,suspensions, syrups and elixirs containing inert diluents commonly usedin the art, such as water and liquid paraffin. Besides inert diluentssuch compositions may also comprise adjuvants, such as wetting,emulsifying and suspending agents, and sweetening, flavouring andaromatizing agents. The compositions according to the invention, fororal administration, also include capsules of absorbable material suchas gelatin containing the active substance with or without the additionof diluents or excipients;

Preparations according to the invention for parenteral administrationinclude sterile aqueous or nonaqueous solutions, suspensions oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil, andinjectable organic esters such as ethyl oleate. These compositions mayalso contain adjuvants such as preserving, wetting, emulsifying anddispersing agents. They may be sterilised by, for example, filtrationthrough a bacteria-retaining filter, by incorporation in thecompositions of sterilising agents, by irradiation, or by heating. Theymay also be manufactured in the form of sterile solid compositions,which can be dissolved in sterile water or some other sterile injectablemedium immediately before use. i

Compositions for rectal administration are suppositories which contain,in addition to the active substance, excipients such as cacao butter ora suitable wax base.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. The dosage depends on thedesired therapeutic effect, on the route of administration and on theduration of the treatment. In human therapy the compositions whenadministered orally to an adult should generally give doses between 100mg. and 1000 mg. of active substance per day.

The following Example illustrates pharmaceutical compositions accordingto the invention.

EXAMPLE 6 Tablets containing 25 mg. of active product and having thefollowing composition are prepared according to the usual technique:

S-phenyll -[2 l-pyrrolidinyl)-ethylamino]-3,4

wherein one of R, and R is hydrogen and the other is phenyl, A isalkylene of l to 5 carbon atoms, and (a) R and R are each alkyl of 1' to5 carbon atoms, or (b) R;, is alkylene forming a 2-piperidyl,3-piperidyl, or 4- piperidyl ring by attachment to a carbon atom of thealkylene A, and R is alkyl of l to 5 carbon atoms, or (c) R, and Rtogether with the nitrogen atom to which they are attached form al-pyrrolidinyl group, and nontoxic acid addition salts thereof.

2. A 3,4-dihydroisoquinoline according to claim 1 wherein A is ethyleneor Z-methyl-ethylene.

3. A 3,4-dihydroisoquinoline according to Claim 1 wherein each of R andR is methyl or ethyl.

4. A 3,4-dihydroisoquinoline according to Claim 1 wherein R is alkyleneattached to a carbon atom of the alkylene radical A to form a3-piperidyl ring and R is ethyl.

5. 3-Phenyll 2-( l-pyrrolidinyl )-ethylamino]-3 ,4- dihydroisoquinolineand non-toxic acid addition salts thereof.

6. l-( 2-Diethylaminopropylamino )-3-phenyl-3 ,4- dihydroisoquinoline,and non-toxic acid addition salts thereof.

7. l-( Z-Diethylaminoethylamino )-3-phenyl-3 ,4- dihydroisoquinoline andnon-toxic acid addition salts thereof.

8. l-( l-Ethyl-3-piperidyl)amino-4-phenyl-3,4- dihydroisoquinoline andnon-toxic acid addition salts thereof.

9. l-( 2-Diethylaminopropylamino )-4-phenyl-3 ,4- dihydroisoquinolineand non-toxic acid addition salts thereof.

2. A 3,4-dihydroisoquinoline according to claim 1 wherein A is ethyleneor 2-methyl-ethylene.
 3. A 3,4-dihydroisoquinoline according to Claim 1wherein each of R3 and R4 is methyl or ethyl.
 4. A3,4-dihydroisoquinoline according to Claim 1 wherein R3 is alkyleneattached to a carbon atom of the alkylene radical A to form a3-piperidyl ring and R4 is ethyl.'''' 5.3-Phenyl-1-(2-(1-pyrrolidinyl)-ethylamino)-3,4-dihyDroisoquinoline andnon-toxic acid addition salts thereof. 6.1-(2-Diethylaminopropylamino)-3-phenyl-3,4-dihydroisoquinoline, andnon-toxic acid addition salts thereof. 7.1-(2-Diethylaminoethylamino)-3-phenyl-3,4-dihydroisoquinoline andnon-toxic acid addition salts thereof. 8.1-(1-Ethyl-3-piperidyl)amino-4-phenyl-3,4-dihydroisoquinoline andnon-toxic acid addition salts thereof. 9.1-(2-Diethylaminopropylamino)-4-phenyl-3,4-dihydroisoquinoline andnon-toxic acid addition salts thereof.